Normalization of obesity-associated insulin resistance through immunotherapy

Winer, S., et al. 2009. Nat. med. 15, 921-930

Speaker: Chia-Chun Tsai (蔡佳純)                                Time: 15:00~16:00, Mar. 31, 2010

Commentator: Dr. Yau-Sheng Tsai (蔡曜聲老師)        Place: Room 601

Abstract:

        Metabolic syndromes related to obesity have become a new threat to public health now, and obesity-associated insulin resistance is a major element of type 2 diabetes development. The adipose tissue inflammation is an important factor of disease progression in type 2 diabetes, but the underlying mechanisms remain unclear. Authors found that high-fat diet (HFD) resulted in a progressive Th1 cell bias and lowered the proportion of Treg cells among fat-associated T cells in the mouse model. The phenomenon in lean and obese humans was strikingly analogous. In addition,antigen-specific expansion of T cell repertoires in the visceral adipose tissue (VAT) probably was driven by obesity. To study the metabolic role of lymphocytes in obesity, authors detected the metabolic profile of Rag1-null mice with the lack of lymphocytes. They found that Rag1-null mice treated with HFD were heavier, and had more impaired glucose tolerance and insulin resistance compared to wild-type mice. Afterward, the adaptive transfer of CD4⁺ T cells (but not CD8⁺ T cells) to Rag1-null mice reversed weight gain and insulin resistance in an antigen-specific fashion. Results showed that the Th2 cells in the VAT of diet-induced obesity (DIO) mice were as a regulator of glucose homeostasis among fat-associated T cells. However, the reduced proportion of Treg cells represented that Treg cells may play a role in DIO-associated metabolic abnormalities. CD3-specific antibody promoted T cell self-tolerance through T cell depletion, paralleled by a selective increase of Treg cells in inflammatory sites¹. The injection of CD3-specific antibody into mice with HFD showed that CD3-specific antibody and its F(ab′)₂ fragment both improved the insulin resistance and glucose tolerance by restoring Treg cells in VAT. Treg cells can induce M2 macrophages, which secreted IL-10 and protected against insulin resistance². Moreover, the treatment of F(ab′)₂ fragment of CD3-specific antibody also increased the numbers of M2 macrophages in VAT. Collectively, the obesity-associated insulin resistance can be normalized through effective immunotherapy.

References:

1. Chatenoud, L., et al. 2007. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat. Rev. Immunol. 7, 622–632.

2. Tiemessen, M.M., et al. 2007. CD4⁺CD25⁺Foxp3⁺ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl. Acad. Sci. USA 104, 19446–19451.